CN110526873B - 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 - Google Patents
氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN110526873B CN110526873B CN201910750761.1A CN201910750761A CN110526873B CN 110526873 B CN110526873 B CN 110526873B CN 201910750761 A CN201910750761 A CN 201910750761A CN 110526873 B CN110526873 B CN 110526873B
- Authority
- CN
- China
- Prior art keywords
- arh
- compound
- cyanovinyl
- amino
- dmso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于医药技术领域,具体为一种氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途。本发明的化合物为氰乙烯基取代的苯并二芳基嘧啶类化合物,还包含其药用盐、水合物及溶剂化物,其多晶或共晶,其同样生物功能的前体和衍生物,还包括其制备方法以及含有一个或多个此类化合物的组合物在治疗艾滋病等相关药物中的应用。体外细胞水平抗HIV‑1活性实验结果显示,该类小分子具有较强的抗HIV‑1生物活性,可以显著的抑制被HIV‑1病毒感染的MT‑4细胞内的病毒复制,并且具有较低的细胞毒性。
Description
技术领域
本发明属于医药技术领域,具体涉及一种氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途。
该系列化合物为HIV-1非核苷类逆转录酶抑制剂,不仅具有较强的生物活性,还具有较小的细胞毒性和较高的选择系数。
背景技术
艾滋病(获得性免疫缺陷综合症)是由人类免疫缺陷病毒(HIV)引发。HIV逆转录酶(RT)在病毒生命周期发挥着重要作用,是设计抗HIV-1药物的重要靶点。RT抑制剂可分为核苷类逆转录酶抑制剂(NRTIs)以及非核苷类逆转录酶抑制剂(NNRTIs)。核苷类逆转录酶抑制剂与底物竞争性的作用于RT活性位点,具有选择性差,毒性高等缺点。非核苷类逆转录酶抑制剂则是以非竞争性的方式结合于距逆转录酶活性位点约距离的变构结合口袋,我们称之为非核苷类逆转录酶抑制剂结合口袋(NNIBP),NNRTIs具有选择型高,活性好等特点,目前临床上使用的NNRTIs主要是第二代HIV抑制剂:二芳基嘧啶类化合物,利匹韦林(Rilpivirine,RPV)和依曲韦林(Etravirine,ETR)。他们存在着水溶性(ETR,<<1μg/mL;RPV,20ng/mL)较差、病人响应率(ETR,36.5%;RPV,27.3%)较低,以及在长期服用中造成的副作用等缺点。另一方面,逆转录酶上的氨基酸突变会使得原本有效的药物失去活性,即产生耐药HIV病毒株,也是限制其临床使用的重要问题。因此,研发具有广谱抗耐药性的新型高效非核苷类逆转录酶抑制剂成为药物化学家们研究的热点之一。
本发明旨在对RPV及ETR进行结构优化,通过引入氰乙烯基结构及苯并嘧啶环来增强化合物与NNIBP内壁氨基酸的非极性相互作用,以期能够提高这一系列化合物对抗耐药病毒株的生物活性。
发明内容
本发明的目的在于提供一种抗HIV-1活性强、细胞毒性低的氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途。
本发明提供的氰乙烯基取代的苯并二芳基嘧啶类化合物,其结构式为:
其中,R1、R2、R3分别独立选自氢,或烷基,烷氧基,烷氧羰基,羟基,卤素,硝基,氨基,烷基氨基,氨基烷基,硝基,氰基,羧基,酰基,酰胺基,三氟甲基,三氟甲氧基,多卤代甲基,多卤代甲氧基,多卤代甲硫基,-NHC(=O)H,或-C(=O)NHNH2,取代或非取代芳香基、取代或非取代杂芳基、饱和或不饱和杂环;
m为0-4,n为0-4。
本发明提供的氰乙烯基取代的苯并二芳基嘧啶类化合物的制备方法,包括两步反应,具体如下:
反应一:在溶剂中,以2,4-二氯喹唑啉衍生物(化合物II)为原料,在碱性条件中,在催化剂和配体催化下,与取代的氰乙烯基苯回流,得化合物III;
反应二:化合物III在溶剂中与取代苯胺反应,得所述化合物I;
其反应通式如下:
反应一中,使用的溶剂为丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺,乙醇,异丙醇,正丁醇,异丁醇中的一种或者多种;
使用的碱为下述无机碱之一种:碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化钠、氢氧化钾、钠氢,或者为下述有机碱之一种:N,N-二甲基氨基吡啶、三乙胺、二异丙基乙基胺、三丁胺、叔丁醇钾中的一种或者多种;
所用催化剂为醋酸钯、氯化钯、四(三苯基膦)钯、二氯二(三苯基膦)钯中的一种或者多种;
配体为2-二环己膦基-2'-(N,N-二甲胺)-联苯、2-二环己基磷-2',4',6'-三异丙基联苯、2-双环己基膦-2',6'-二甲氧基联苯中的一种或者多种;
化合物II、取代的氰乙烯基苯、与碱的摩尔比为1:1:1.5-1:1.5:3(1:(1-1.5):(1.5-3)),最优摩尔比例为1:1.2:2;所述的化合物II、催化剂与配体的摩尔比为1:0.05:0.1-1:0.1:0.3(1:(0.05-0.1):(0.1-0.3)),最优摩尔比例为1:0.05:0.1;
反应温度为30~140℃;
反应时间为4~14h。
反应二中,所用溶剂为丙酮、乙腈、甲苯、二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺,乙醇,异丙醇,正丁醇,异丁醇中的一种或者多种;
所述的化合物III、取代苯胺摩尔比为1:1.5-1:3(1:(1.5-3)),最优摩尔比例为1:2;
反应温度为30~140℃;
反应时间为4~14h。
本发明还涉及一种药物组合物,该组合物含有有效剂量的上述化合物和相关的药用载体。
本发明还涉及上述氰乙烯基取代的苯并二芳基嘧啶类化合物的药用盐,包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、柠檬酸盐、富马酸盐或苹果酸盐,以及药学上可接受的前体药物和衍生物。
本发明还涉及上述氰乙烯基取代的苯并二芳基嘧啶类化合物的水合物及溶剂化物,其多晶或共晶,其同样生物功能的前体和衍生物。
本发明还涉及上述化合物或其药用盐或组合物在制备预防和治疗艾滋病药物中的应用。
本发明基于氰乙烯基取代的苯并二芳基嘧啶类化合物与HIV逆转录酶的结合模式,结合计算机辅助药物设计,在嘧啶母环上引入带取代基的苯环结构,增强化合物与结合口袋中氨基酸残基V179,E138之间的非极性相互作用。同时左翼上氰乙烯基结构能深入结合口袋加强与高度保守氨基酸残基Phe227,Trp229之间的结合力,进一步提高目标化合物抗耐药HIV病毒株的生物活性。体外细胞水平抗HIV-1活性实验结果显示,该系列化合物具有较显著的抗HIV-1活性,并且具有较低的细胞毒性。
具体实施方式
通过下述实施实例可以更好地理解本发明内容,但是不能限制本发明的内容。
化合物II的合成:
反式-3-(4-氨基-3,5-二取代苯基)丙烯腈(10mmol),取代2,4-二氯喹唑啉(13mmol),醋酸钯(112mg,0.5mmol),2-二环己膦基-2'-(N,N-二甲胺)-联苯(394mg,1mmol),磷酸钾(6.37g,30mmol)in N,N-二甲基甲酰胺(80mL)在氮气保护下在140℃中加热12小时。TLC显示反应完全。依次用乙酸乙酯稀释(10mL)、饱和碳酸钠溶液(10mL×2)、水(10mL×2)、饱和食盐水(10mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,柱色谱分离,得到目标化合物III。
以不同的2,4-二氯喹唑啉(化合物Ⅱ)和反式-3-(4-氨基-3,5-二取代苯基)丙烯腈用上述方法分别制得不同目标化合物III,部分结果如下。
实施例1:反式-3-(4-((2-氯喹唑啉-4-)氨基)-3,5-二甲基苯基)丙烯腈的合成
反式-3-(4-氨基-3,5-二甲基苯基)丙烯腈(334.8mg,10mmol),2,4-二氯喹唑啉(258.7mg,13mmol),醋酸钯(112mg,0.5mmol),2-二环己膦基-2'-(N,N-二甲胺)-联苯(394mg,1mmol),磷酸钾(6.37g,30mmol)in N,N-二甲基甲酰胺(80mL)在氮气保护下在140℃中加热12小时。TLC显示反应完全。依次用乙酸乙酯稀释(10mL)、饱和碳酸钠溶液(10mL×2)、水(10mL×2)、饱和食盐水(10mL×2)洗涤,有机相经无水硫酸钠干燥过夜。过滤,浓缩,柱色谱分离,得到所需固体。
收率23%,白色固体;1H NMR(400MHz,DMSO-d6)δ10.15(s,1H,NH),8.54(d,J=8.1Hz,1H,ArH),7.89(t,J=7.6Hz,1H,ArH),7.72(d,J=8.2Hz,1H,ArH),7.68–7.58(m,2H,ArH and olefinic H),7.51(s,2H,ArH),6.47(d,J=16.8Hz,1H,olefinic H),2.18(s,6H,CH3×2);13C NMR(101MHz,DMSO-d6)δ160.38,156.74,150.62,150.12,137.73,136.50,134.14,132.56,127.43,126.80,126.66,123.42,118.85,113.17,109.49,96.74,18.00.LCMS(ESI,M+1):335.2。
化合物III的合成:
化合物II(2mmol),取代苯胺(4mmol)在正丁醇(5mL)中回流6-8小时。反应液中析出不溶物,过滤,并用二氯甲烷洗涤(5mL×3),干燥,以37-55%的收率得到化合物III。
化合物III在溶剂中与取代苯胺反应,得所述化合物I。
以不同的化合物III和取代苯胺用上述方法分别制得不同目标化合物I,部分结果如下。
实施例2:反式-4-((6-氯-4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
化合物II反式-3-(4-((2,6-二氯喹唑啉-4-)氨基)-3,5-二氟苯基)丙烯腈(2mmol),对氨基苯腈(4mmol,472mg)在正丁醇(5mL)中回流6-8小时。反应液中析出不溶物,过滤,并用二氯甲烷洗涤(5mL×3),干燥,得到化合物I反式-4-((6-氯-4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)喹唑啉-2-)氨基)苯腈。
收率41%,白色固体,熔点>325℃;1H NMR(400MHz,DMSO-d6)δ11.61(s,1H,NH),10.76(s,1H,NH),8.84(s,1H,ArH),8.07(s,2H,ArH),7.96(d,J=8.6Hz,1H,ArH),7.82–7.69(m,2H,ArH andolefinic H),7.53(s,4H),6.81(d,J=16.8Hz,1H,olefinic H).13CNMR(101MHz,DMSO-d6)δ160.18,153.38,147.77,142.99,136.15,135.04,134.80,133.15,129.23,128.31,124.17,120.72,119.44,118.63,111.85,105.25,101.11.HRMS calcd forC24H13Cl3N6[M+H]+:491.0340,found:491.0338.HPLC analysis:tR=21.15min,96.42%。
实施例3:反式-4-((6-氯-4-((4-(2-氰乙烯基)-2-氟-6-甲基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率52%,黄色固体,熔点278-282℃.1H NMR(400MHz,DMSO-d6)δ10.98(s,1H,NH),10.56(s,1H,NH),8.81–8.74(m,1H,NH),8.04–7.52(m,9H,ArHandolefinic H),6.36(d,14.2Hz,1H,olefinic H),2.31(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.29,157.06,149.47(d,JC-F=2.5Hz),143.22,139.19,135.79,134.84,133.44(d,JC-F=11.7Hz),133.17,129.01,126.65(d,JC-F=2.1Hz),124.20,120.54,119.51,118.96,112.63(d,JC-F=22.0Hz),112.17,99.10,18.12(d,JC-F=2.3Hz).HRMScalcd for C25H16ClFN6[M+H]+:455.1182,found:455.1168.HPLC analysis:tR=19.25min,95.01%。
实施例4:反式-4-((6-氯-4-((4-(2-氰乙烯基)-2-甲基-6-硝基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率51%,黄色固体,熔点324-326°;1H NMR(400MHz,DMSO-d6)δ11.56(s,1H,NH),10.72(s,1H,NH),8.84(s,1H,ArH),8.31(s,1H,ArH),8.14(s,1H,ArH),7.99–7.70(m,3H,ArH andolefinic H),7.62–7.42(m,4H,ArH),6.79(d,J=16.5Hz,1H,olefinic H),2.37(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.29,153.01,148.34,147.66,142.75,140.23,136.22,134.54,134.32,133.18,131.50,129.34,124.37,123.18,122.50,120.88,119.41,118.73,112.11,105.46,100.66,18.45.HRMS calcd forC25H16ClN7O2[M+H]+:482.1127,found:482.1125.HPLC analysis:tR=19.08min,95.05%。
实施例5:反式-4-((4-((2,6-二氯-4-(2-氰乙烯基)苯基)氨基)-6-氟喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率49%,淡黄色固体,熔点>325°;1H NMR(400MHz,DMSO-d6)δ11.28(s,1H,NH),10.53(s,1H,NH),8.51(d,J=8.9Hz,1H,ArH),8.15–7.99(m,2H,ArH),7.97–7.48(m,7H,ArH andolefinic H),6.80(d,J=16.8Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.34(d,JC-F=3.2Hz),158.53(d,JC-F=244.2Hz),151.73,147.22,141.85,135.87,134.23,133.13,132.86,132.70,127.84,125.06(d,JC-F=25.1Hz),122.34(d,JC-F=8.4Hz),120.64,118.78,118.11,110.68(d,JC-F=8.9Hz),109.93(d,JC-F=24.3Hz),105.41,100.77,40.15,39.94,39.73,39.52,39.31,39.10,38.89.HRMS calcdfor C24H13Cl2FN6[M+H]+:475.0636,found:475.0630.HPLC analysis:tR=17.83min,95.10%。
实施例6:反式-4-((4-((2-氯-4-(2-氰乙烯基)-6-氟苯基)氨基)-6-氟喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率45%,白色固体,熔点297-299°;1H NMR(400MHz,DMSO-d6)δ11.53(s,1H,NH),10.78(s,1H,NH),8.64(s,1H,ArH),7.93–7.85(m,3H,ArH),7.82–7.72(m,2H,ArH andolefinic H),7.55(dd,J=20.5,8.3Hz,4H,ArH),6.78(d,J=16.8Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.89(d,JC-F=3.1Hz),160.09(d,JC-F=5.5Hz),157.63(d,JC-F=11.7Hz),152.76,148.05,142.73,136.19(d,JC-F=9.1Hz),133.99,133.96,133.22,125.78,125.75,125.26(d,JC-F=23.9Hz),123.47,121.02,119.39,118.59,114.53(d,JC-F=21.7Hz),111.41(d,JC-F=8.7Hz),110.14(d,JC-F=26.6Hz),105.54,100.96.HRMS calcd for C24H13ClF2N6[M+H]+:459.0931,found:459.0932.HPLCanalysis:tR=17.58min,98.35%。
实施例7:反式-4-((4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)-6-氟喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率48%,淡黄色固体,熔点293-299°;1H NMR(400MHz,DMSO-d6)δ10.98(s,1H,NH),10.52(s,1H,NH),8.51(d,J=9.0Hz,1H,ArH),8.14–7.69(m,6H,ArHandolefinic H),7.69–7.58(m,3H,ArH),6.74(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.64,159.88,159.69,157.46,157.19(d,JC-F=4.8Hz),153.66,148.38,143.50,133.47(d,JC-F=16.5Hz),133.22,124.94,124.68,123.84,120.51,119.61,118.62,112.05(d,JC-F=24.3Hz),111.72,109.61(d,JC-F=24.5Hz),106.58,104.77,104.68,100.56.HRMS calcd forC24H13F3N6[M+H]+:443.1227,found:443.1218.HPLC analysis:tR=16.99min,95.05%。
实施例8:反式-4-((4-((4-(2-氰乙烯基)-2-氟-6-甲基苯基)氨基)-6-氟喹唑啉-2-)氨基苯腈的合成。该化合物的结构式为:
操作方法同上。收率47%,淡黄色固体,熔点284-288°;1H NMR(400MHz,DMSO-d6)δ11.60(s,1H,NH),10.91(s,1H,NH),8.78(d,J=9.0Hz,1H,ArH),8.12–7.67(m,5H,ArHandolefinic H),7.59–7.51(m,3H,ArH),7.50–7.44(m,2H,ArH),6.67(d,J=16.6Hz,1H,olefinic H),2.32(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.99(d,JC-F=3.2Hz),160.23,158.171(d,JC-F=248.9Hz),157.80,152.07,149.39,142.29,139.14,135.17(d,JC-F=8.7Hz),133.22,126.66,126.31(d,JC-F=13.4Hz),125.22(d,JC-F=24.3Hz),122.16(d,JC-F=6.2Hz),121.11,119.10(d,JC-F=36.8Hz),112.63(d,JC-F=21.7Hz),111.58(d,JC-F=8.7Hz),110.73(d,JC-F=25.1Hz),105.92,99.27,18.11(d,JC-F=2.2Hz).HRMS calcdfor C25H16F2N6[M+H]+:439.1477,found:439.1470.HPLC analysis:tR=15.42min,95.05%。
实施例9:反式-4-((4-((4-(2-氰乙烯基)-2-甲基-6-硝基苯基氨基)-6-氟喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率47%,黄色固体,熔点294-298°;1H NMR(400MHz,DMSO-d6)δ11.73(s,1H,NH),10.78(s,1H,NH),8.66(d,J=8.8Hz,1H,ArH),8.31(s,1H,ArH),8.14(s,1H,ArH),7.90–7.44(m,7H,ArH andolefinic H),6.80(d,J=16.6Hz,1H,olefinic H),2.38(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.80,158.92(d,JC-F=242.1Hz),152.42,148.31,147.69,142.57,140.22,134.56,134.42,133.60,133.37,133.19,131.35,122.50,121.01,119.36,118.72,111.57,105.64,100.72,18.44.HRMS calcd for C25H16FN7O2[M+H]+:466.1416,found:466.1421.HPLC analysis:tR=15.48min,95.01%。
实施例10:反式-4-((4-((4-(2-氰乙烯基)-2,6-二甲基苯基)氨基)-6-甲氧基喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率46%,淡黄色固体,熔点303-308°;1H NMR(400MHz,DMSO-d6)δ11.45(s,1H,NH),10.77(s,1H,NH),8.32(s,1H,ArH),7.75(d,J=16.8Hz,1H,olefinic H),7.69–7.54(m,4H,ArH),7.42(dd,J=22.6,8.5Hz,4H,ArH),6.58(d,J=16.8Hz,1H,olefinic H),3.96(s,3H,OCH3),2.23(s,6H,CH3×2).13C NMR(101MHz,CDCl3)δ160.58,157.22,150.98,150.57,142.68,138.11,136.84,133.71,133.17,128.94,128.06,126.40,120.81,120.28,119.32,111.33,106.11,105.35,97.64,56.86,18.41.HRMS calcd forC27H22N6O[M+H]+:447.1928,found:447.1940.HPLC analysis:tR=12.95min,97.30%。
实施例11:反式-4-((4-((2,6-二氯-4-(2-氰乙烯基)苯基)氨基)-6-甲氧基喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率47%,黄色固体,熔点156-159°;1H NMR(400MHz,DMSO-d6)δ11.95(s,1H,NH),10.90(s,1H,NH),8.33(s,1H,ArH),8.15(s,2H,ArH),7.69(dd,J=31.4,8.5Hz,2H,ArH),7.59(d,J=12.1Hz,1H,olefinic H),7.49(dd,J=38.1,8.4Hz,4H,ArH),6.26(d,J=12.1Hz,1H,olefinic H),3.96(s,3H,OCH3).13C NMR(101MHz,DMSO-d6)δ160.86,157.37,150.98,145.96,142.39,136.35,136.12,134.80,134.65,133.44,133.17,129.09,127.27,121.28,120.74,119.21,117.53,111.02,105.72,100.23,56.90.HRMScalcd for C25H16Cl2N6O[M+H]+:487.0835,found:487.0837.HPLC analysis:tR=17.97min,95.03%。
实施例12:反式-4-((4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)-6-甲氧基喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率53%,淡黄色固体,熔点301-305°;1H NMR(400MHz,DMSO-d6)δ11.67(s,1H,NH),10.85(s,1H,NH),8.31(s,1H,ArH),7.79–7.67(m,4H,ArH andolefinicH),7.66–7.47(m,5H,ArH),6.76(d,J=16.6Hz,1H,olefinic H),3.94(s,3H,OCH3).13C NMR(101MHz,DMSO-d6)δ161.02,159.58(d,JC-F=5.0Hz),157.29,157.10(d,JC-F=5.5Hz),151.15,148.29,142.33,135.74(t,JC-F=9.0Hz),133.28,127.27,121.17,119.33,118.58,116.63(t,JC-F=17.7Hz),112.08(d,JC-F=23.8Hz),111.38,105.88,105.71,100.78,56.90.HRMS calcd forC25H16F2N6O[M+H]+:455.1426,found:455.1417.HPLC analysis:tR=13.89min,96.94%。
实施例13:反式-4-((4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)-6-羟基喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
收率41%,黄色固体,熔点>325°;1H NMR(400MHz,DMSO-d6)δ9.79(s,1H,NH),9.69(s,1H,NH),9.54(s,1H,OH),7.87–7.59(m,6H,ArH andolefinic H),7.59–7.45(m,3H,ArH),7.41–7.32(m,1H,ArH),6.70(d,J=16.5Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.07,159.63,157.59,154.18,153.87,148.61,145.62,134.42,133.11,126.66,125.78,120.15,118.73,112.47,111.94(d,JC-F=23.4Hz),110.01,106.44,102.29,100.06.HRMS calcd for C24H14F2N6O[M+H]+:441.1270,found:441.1265.HPLC analysis:tR=10.23min,95.04%。
实施例14:反式-4-((4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)-6-硝基喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率47%,黄色固体,熔点320-325°;1H NMR(400MHz,DMSO-d6)δ10.96(s,1H,NH),10.42(s,1H,NH),9.55(s,1H,ArH),8.51(d,J=8.9Hz,1H,ArH),7.84–7.66(m,6H,ArH andolefinic H),7.65–7.55(m,2H,ArH),6.74(d,J=16.6Hz,1H,olefinicH).13C NMR(101MHz,DMSO-d6)δ161.27,159.69(d,JC-F=5.2Hz),157.21(d,JC-F=5.5Hz),148.44,144.11,142.69,135.08(t,JC-F=9.6Hz),133.92,133.17,128.58,125.88,122.02,120.18,119.70,118.66,117.31(t,JC-F=16.2Hz),112.07(d,JC-F=23.8Hz),110.71,104.35,100.44.HRMS calcd for C24H13F2N7O2[M+Na]+:492.0991,found:492.0995.HPLCanalysis:tR=20.72min,98.63%。
实施例15:反式-4-((7-氯-4-((2,6-二氯-4-(2-氰乙烯基)苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率55%,淡黄色固体,熔点>325°;1H NMR(400MHz,DMSO-d6)δ11.02(s,1H,NH),10.37(s,1H,NH),8.54(d,J=8.7Hz,1H,ArH),8.05(s,2H,ArH),7.81–7.47(m,7H,ArH andolefinic H),6.79(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.70,153.40,147.74,142.76,140.82,136.20,135.03,134.82,133.13,128.29,127.05,125.78,120.97,120.40,119.37,118.61,109.54,105.51,101.15.HRMScalcd for C24H13Cl3N6[M+H]+:491.0340,found:491.0333.HPLC analysis:tR=15.42min,95.03%。
实施例16:反式-4-((7-氯-4-((2-氯-4-(2-氰乙烯基)-6-氟苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率40%,白色固体,熔点304-306°;1H NMR(400MHz,DMSO-d6)δ11.24(s,1H,NH),10.69(s,1H,NH),8.67(d,J=8.8Hz,1H,ArH),7.91(s,1H,ArH),7.87(d,J=10.4Hz,1H,ArH),7.79–7.71(m,2H,ArH andolefinic H),7.68–7.50(m,5H,ArH),6.77(d,J=16.8Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.81,160.16,157.65,153.89,148.08,140.58,136.05(d,JC-F=9.1Hz),134.08(d,JC-F=2.9Hz),133.17,126.97,125.65(d,JC-F=21.6Hz),120.88,119.46,118.61,114.50(d,JC-F=21.8Hz),109.82,100.88.HRMS calcd forC24H13Cl2FN6[M+H]+:475.0636,found:475.0632.HPLC analysis:tR=20.95min,95.10%。
实施例17:反式-4-((7-氯-4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率49%,白色固体,熔点318-322°;1H NMR(400MHz,DMSO-d6)δ10.59(s,1H,NH),10.21(s,1H,NH),8.50(d,J=8.7Hz,1H,ArH),7.81–7.68(m,4H,ArHandolefinic H),7.66–7.54(m,5H,ArH),6.73(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ160.79,159.68(d,JC-F=5.7Hz),157.20(d,JC-F=5.5Hz),154.23,148.36,143.23,140.41,135.40(t,JC-F=9.0Hz),133.44(d,JC-F=19.0Hz),133.21,126.93,125.37,120.83,119.53,118.61,116.99(t,JC-F=16.7Hz),112.04(d,JC-F=23.8Hz),110.07,105.11,100.60.HRMS calcd for C24H13ClF2N6[M+H]+:459.0931,found:459.0932.HPLC analysis:tR=25.58min,98.28%。
实施例18:反式-4-((7-氯-4-((4-(2-氰乙烯基)-2-氟-6-甲基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率43%,白色固体,熔点248-251°;1H NMR(400MHz,DMSO-d6)δ11.37(s,1H,NH),10.82(s,1H,NH),8.77(d,J=8.8Hz,1H,ArH),7.79–7.61(m,4H,ArHandolefinic H),7.58–7.50(m,5H,ArH),6.66(d,J=16.6Hz,1H,olefinic H),2.30(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.89,158.25(d,JC-F=247.5Hz),153.20,149.45,142.69,140.63,139.21,135.03(d,JC-F=8.7Hz),133.18,127.29,126.65,126.52,125.66,120.99,119.75,119.16(d,JC-F=43.8Hz),112.63(d,JC-F=21.7Hz),109.89,105.59,99.19,18.11(d,JC-F=2.0Hz).HRMS calcd for C25H16ClFN6[M+H]+:455.1182,found:455.1182.HPLC analysis:tR=23.80min,95.19%。
实施例19:反式-4-((7-氯-4-((4-(2-氰乙烯基)-2-甲基-6-硝基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率49%,黄色固体,熔点287-289°;1H NMR(400MHz,DMSO-d6)δ11.38(s,1H,NH),10.62(s,1H,NH),8.64(d,J=8.7Hz,1H,ArH),8.29(s,1H,ArH),8.12(s,1H,ArH),7.83(d,J=16.6Hz,1H,olefinic H),7.75(s,1H,ArH),7.62(d,J=8.8Hz,1H,ArH),7.53(s,4H,ArH),6.77(d,J=16.6Hz,1H,olefinic H),2.35(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.66,153.76,148.37,147.73,140.51,140.23,134.48,134.20,133.15,127.01,125.50,122.48,120.79,119.48,118.75,110.04,105.22,100.59,18.46.HRMS calcd for C25H16ClN7O2[M+H]+:482.1127,found:482.1122.HPLC analysis:tR=12.57min,95.01%。
实施例20:反式-4-((4-((2-氨基-4-(2-氰乙烯基)-6-甲基苯基)氨基)-7-氯喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
收率46%,黄色固体,熔点210-213°;1H NMR(400MHz,DMSO-d6)δ9.72(s,1H,NH),9.47(s,1H,NH),8.40(d,J=8.6Hz,1H,ArH),7.84(d,J=7.3Hz,2H,ArH),7.60(d,J=16.6Hz,1H,olefinic H),7.53(s,1H,ArH),7.42(d,J=7.9Hz,2H,ArH),7.36(d,J=8.1Hz,1H,ArH),6.90(s,2H,ArH),6.32(d,J=16.6Hz,1H,olefinic H),5.21(s,2H,NH2),2.09(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ160.62,157.76,152.93,151.72,146.64,146.05,138.17,137.64,133.27,132.89,126.42,125.22,124.56,122.92,120.19,119.57,118.84,117.18,112.56,111.20,101.98,96.12,18.60.HRMS calcd for C25H18ClN7[M+H]+:452.1385,found:452.1381.HPLC analysis:tR=20.82min,95.41%。
实施例21:反式-4-((4-((4-(2-氰乙烯基)-2,6-二甲基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率38%,白色固体,熔点280-284°;1H NMR(400MHz,DMSO-d6)δ11.33(s,1H,NH),10.85(s,1H,NH),8.67(d,J=7.9Hz,1H,ArH),7.95(t,J=7.5Hz,1H,ArH),7.77–7.65(m,2H,ArH and olefinic H),7.64–7.55(m,3H,ArH),7.42(dd,J=19.3,8.1Hz,4H,ArH),6.57(d,J=16.6Hz,1H,olefinic H),2.21(s,6H,CH3×2).13C NMR(101MHz,DMSO-d6)δ160.49,151.53,150.05,142.03,137.54,136.33,135.88,133.24,132.66,127.54,125.26,124.62,120.01,118.79,110.23,105.07,97.17,17.86.HRMScalcd for C26H20N6[M+H]+:417.1822,found:417.1813.HPLC analysis:tR=15.03min,95.69%。
实施例22:反式-4-((4-((2,6-二氯-4-(2-氰乙烯基)苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率52%,白色固体,熔点>325°;1H NMR(400MHz,DMSO-d6)δ11.73(s,1H,NH),10.92(s,1H,NH),8.67(d,J=8.2Hz,1H,ArH),8.09(s,2H,ArH),7.99(t,J=7.7Hz,1H,ArH),7.81–7.71(m,2H,ArH andolefinic H),7.63(t,J=7.6Hz,1H,ArH),7.51(dd,J=33.7,8.4Hz,4H,ArH),6.83(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ161.23,147.73,142.38,136.78,136.33,134.93,134.78,133.21,128.32,125.97,125.07,121.07,119.29,118.61,110.46,101.22.HRMS calcd for C24H14Cl2N6[M+H]+:457.0730,found:457.0729.HPLC analysis:tR=12.57min,99.09%。
实施例23:反式-4-((4-((2-氯-4-(2-氰乙烯基)-6-氟苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率51%,白色固体,熔点304-308°;1H NMR(400MHz,DMSO-d6)δ11.63(s,1H,NH),10.94(s,1H,NH),8.69(d,J=8.2Hz,1H,NH),7.97(t,J=7.8Hz,1H,ArH)),7.93(s,1H,ArH)),7.89(d,J=10.3Hz,1H,ArH)),7.78–7.72(m,2H,ArHandolefinic H),7.63–7.45(m,5H,ArH)),6.79(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ161.45,160.06,157.57,152.34,148.04,142.30,136.80,136.26,134.03(d,JC-F=2.7Hz),133.25,125.86(d,JC-F=22.3Hz),125.18,121.27,118.94(d,JC-F=70.9Hz),114.54(d,JC-F=21.7Hz),110.62,101.04.HRMS calcd for C24H14ClFN6[M+H]+:441.1025,found:441.1018.HPLC analysis:tR=12.20min,97.85%。
实施例24:反式-4-((4-((4-(2-氰乙烯基)-2,6-二氟苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率39%,白色固体,熔点306-312°;1H NMR(400MHz,DMSO-d6)δ11.74(s,1H,NH),11.06(s,1H,NH),8.76(d,J=7.9Hz,1H,ArH),7.98(t,J=1.8Hz,1H,ArH),7.84–7.71(m,4H,ArH andolefinic H),7.70–7.57(m,3H,ArH),7.55–7.47(m,2H,ArH),6.78(d,J=16.6Hz,1H,olefinic H).13C NMR(101MHz,DMSO-d6)δ161.60,159.59(d,JC-F=5.2Hz),157.10(d,JC-F=5.2Hz),152.11,148.27,142.02,136.89,135.87(t,JC-F=9.9Hz),133.31,126.03,125.42,121.49,119.43,119.26,118.57,116.53(t,JC-F=17.0Hz),112.07(d,JC-F=23.4Hz),110.74,106.30,100.86.HRMS calcd for C24H14F2N6[M+H]+:425.1321,found:425.1314.HPLC analysis:tR=15.80min,95.49%。
实施例25:反式-4-((4-((4-(2-氰乙烯基)-2-氟-6-甲基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率50%,白色固体,熔点286-292°;1H NMR(400MHz,DMSO-d6)δ11.33(s,1H,NH),10.83(s,1H,NH),8.69(d,J=7.9Hz,1H,ArH),8.08–7.47(m,10H,ArHandolefinic H),6.66(d,J=16.8Hz,1H,olefinic H),2.31(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ161.38,152.30,149.43,142.50,139.24,139.09,136.49,135.12(d,JC-F=9.7Hz),133.48(d,JC-F=17.8Hz),133.22,126.64,125.79,125.08,121.07,119.15(d,JC-F=40.9Hz),112.63(d,JC-F=17.7Hz),110.79,99.24,18.04(d,JC-F=1.7Hz).HRMS calcdfor C25H17FN6[M+H]+:421.1571,found:421.1568.HPLC analysis:tR=14.87min,95.04%。
实施例26:反式-4-((4-((4-(2-氰乙烯基)-2-甲基-6-硝基苯基)氨基)喹唑啉-2-)氨基)苯腈的合成。该化合物的结构式为:
操作方法同上。收率53%,黄色固体,熔点285-288°;1H NMR(400MHz,DMSO-d6)δ11.51(s,1H,NH),10.88(s,1H,NH),8.67(d,J=7.9Hz,1H,ArH),8.31(s,1H,ArH),8.14(s,1H,ArH),8.02–7.91(m,1H,ArH),7.84(d,J=16.6Hz,1H,olefinic H),7.71(d,J=8.2Hz,1H,ArH),7.62(t,J=7.3Hz,1H,ArH),7.57–7.32(m,4H,ArH),6.79(d,J=16.8Hz,1H,olefinic H),2.36(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ161.35,152.15,148.32,147.76,140.27,136.71,134.56,133.21,131.50,125.95,125.25,122.49,121.16,119.30,118.72,110.81,110.01,105.97,100.76,18.40.HRMS calcd for C25H17N7O2[M+H]+:448.1516,found:448.1506.HPLC analysis:tR=10.55min,98.89%。
实施例27:抗HIV生物活性测试
体外细胞水平的抗HIV病毒活性由比利时Katholleke大学的Rega药物研究所测定,主要包括:对HIV感染的MT-4细胞的抑制活性及细胞毒性两方面。方法如下:使化合物在HIV感染的MT-4细胞中,于感染HIV不同时间,用MTT法测定药物对HIV诱变的细胞病变的保护作用,计算使50%的细胞免于HIV诱导的细胞病变所需的浓度半数有效浓度EC50,毒性测定与抗HIV活性实验平行进行,也是在MT-4细胞培养中,用MTT法测定使50%的未感染细胞发生细胞病变的浓度(CC50),并计算选择性指数SI=CC50/EC50。
材料与方法:
各化合物的抗HIV活性由药物对HIV在细胞中引起的细胞病变的抑制作用效率来监控。采用MT-4细胞进行细胞培养。采用的病毒株有:HIV-1病毒株ⅢB及HIV-2病毒株ROD。
具体操作如下:将化合物用DMSO或水溶解后在磷酸盐缓冲食盐水溶液稀释,将3×105MT-4细胞用100μL各化合物不同浓度此溶液在37℃预培养1h,然后向该化合物中加入100μL适当的病毒稀释液,将细胞于37℃培养1h。洗涤三次后,将细胞再次分别悬浮于含有或不含有化合物的培养介质中。接着将细胞在5%CO2氛围中,于37℃下再培养7天,并于感染后第三天用含有或不含有化合物的培养介质替换补充培养液。每种培养液条件重复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。典型来讲,本实验中所用的病毒稀释液常常会在病毒感染后第五天导致细胞病变。药物抑制浓度以药物对病毒细胞病变作用产生50%抑制作用而同时对细胞无直接毒性的浓度(CC50)表示。需要强调的是,当化合物水溶性较差,需要DMSO才能溶解时,DMSO比浓度相对于水来讲,一般低于10%(DMSO在MT-4细胞培养介质中最终浓度小于2%)。因为DMSO能影响测试化合物的抗病毒活性,对含有相同浓度DMSO溶液抗病毒活性对比空白实验也应该平行进行。另外,DMSO最终浓度(1/1000)远远低于HIV-1在T细胞中复制所需的浓度。
本发明用已上市药物奈维拉平(Nevirapine,NVP)、依非韦伦(Efavirenz,EFV)和依曲韦林(Etravirine,ETR)作对照品,部分目标化合物对HIV的抑制活性结果见表1(实施例2~实施例26在MT-4细胞中的抗HIV活性和细胞毒性)。
表1a
aAll data represent mean values of at least three separateexperiments.bEC50:effective concentration required to protect 50%of cellsagainst viral cytopathicity in MT-4cells.cCC50:cytotoxic concentration of thecompound that reduces the normal uninfected MT-4cell viability by 50%.dSI:selectivity index,ratio CC50/EC50(WT)。
实验结果表明,化学通式中所包含的化合物普遍具有较强的抗HIV-1病毒活性,较小的细胞毒性和较高的选择性指数。
本发明不限于上述实例。
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910750761.1A CN110526873B (zh) | 2019-08-15 | 2019-08-15 | 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910750761.1A CN110526873B (zh) | 2019-08-15 | 2019-08-15 | 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110526873A CN110526873A (zh) | 2019-12-03 |
CN110526873B true CN110526873B (zh) | 2022-09-16 |
Family
ID=68663244
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910750761.1A Active CN110526873B (zh) | 2019-08-15 | 2019-08-15 | 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110526873B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1681774A (zh) * | 2002-08-09 | 2005-10-12 | 詹森药业有限公司 | 制备4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苄腈的方法 |
CN1856496A (zh) * | 2003-09-25 | 2006-11-01 | 詹森药业有限公司 | 抑制hiv复制的嘌呤衍生物 |
CN101463014A (zh) * | 2008-12-26 | 2009-06-24 | 复旦大学 | 二芳基苯并嘧啶类衍生物及其制备方法和用途 |
CN101816658A (zh) * | 2001-08-13 | 2010-09-01 | 詹森药业有限公司 | 抑制hiv的嘧啶衍生物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9139535B2 (en) * | 2012-07-12 | 2015-09-22 | Hetero Research Foundation | Process for rilpivirine using novel intermediate |
-
2019
- 2019-08-15 CN CN201910750761.1A patent/CN110526873B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101816658A (zh) * | 2001-08-13 | 2010-09-01 | 詹森药业有限公司 | 抑制hiv的嘧啶衍生物 |
CN1681774A (zh) * | 2002-08-09 | 2005-10-12 | 詹森药业有限公司 | 制备4-[[4-[[4-(2-氰基乙烯基)-2,6-二甲基苯基]氨基]-2-嘧啶基]氨基]苄腈的方法 |
CN1856496A (zh) * | 2003-09-25 | 2006-11-01 | 詹森药业有限公司 | 抑制hiv复制的嘌呤衍生物 |
CN101463014A (zh) * | 2008-12-26 | 2009-06-24 | 复旦大学 | 二芳基苯并嘧啶类衍生物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
CN110526873A (zh) | 2019-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2007281604A1 (en) | HIV reverse transcriptase inhibitors | |
KR102383938B1 (ko) | 신규한 매크로시클릭 화합물 | |
KR20150084968A (ko) | 술폭시민 기를 함유하는 5-플루오로-n-(피리딘-2-일)피리딘-2-아민 유도체 | |
WO2008112156A1 (en) | Chemokine receptor modulators | |
CN101121698B (zh) | 二芳基嘧啶类衍生物及其制备方法和用途 | |
US11912685B2 (en) | Biphenyl diaryl pyrimidine derivative with aromatic heterocyclic structure | |
CN106831605B (zh) | 一种取代二芳基嘧啶类衍生物及其制备方法与应用 | |
KR20150082604A (ko) | 술폭시민 기를 함유하는 n-(피리딘-2-일)피리미딘-4-아민 유도체 | |
CN108218890A (zh) | 一种五元非芳环并嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 | |
CN101463014B (zh) | 二芳基苯并嘧啶类衍生物及其药物组合物和用途 | |
AU2012300274B2 (en) | HIV replication inhibitors | |
CN109053591A (zh) | 含联苯结构的二芳基嘧啶类衍生物及其制备方法和用途 | |
JP3539926B2 (ja) | 抗ウイルス性ピリミジンジオン誘導体及びそれらの製造方法 | |
US11447501B2 (en) | Biphenyl-containing diarylpyrimido compounds, pharmaceutically-acceptable salts thereof, composition and preparation thereof | |
CN113461666A (zh) | 含芳杂环结构的联苯二芳基甲基嘧啶衍生物及其制备方法 | |
CN112624983A (zh) | 一种含烷基结构的联苯二芳基嘧啶类衍生物及其制备方法和应用 | |
CN109369623B (zh) | 一种取代1,2,3三氮唑类二芳基嘧啶衍生物及其制备方法与应用 | |
CN110526873B (zh) | 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 | |
CN111675661A (zh) | 一种含有反式双键的二芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 | |
Marich et al. | Synthesis, anti-HIV activity and molecular modeling study of some new pyrimidine analogues | |
CN101759684A (zh) | 二芳基嘧啶类衍生物及其制备方法和用途 | |
CN108586482A (zh) | 一种含三氮唑环的二芳基嘧啶类hiv-1抑制剂及其制备方法和应用 | |
CN108409734A (zh) | 吡啶并嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 | |
CN101723903A (zh) | 4-羰基二芳基嘧啶类衍生物及其制备方法和用途 | |
Costi et al. | Structure-activity relationship studies on potential non-nucleoside DABO-like inhibitors of HIV-1 reverse transcriptase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |